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Restless Legs Syndrome (RLS) can be very difficult to recognize and
diagnose. Patients who suffer from this malady describe an intense,
uncomfortable sensation in the legs accompanied by an irresistible need to
move the legs, thus temporarily relieving their distress. This article
focuses on diagnoses, symptoms, pathophysiology, and treatment of RLS.
Introduction. Restless Legs Syndrome (RLS) can be very difficult to
recognize and diagnose, as the diagnosis relies heavily on the description
of the problem rather than any particular signs of the neurological
examination. Patients who suffer from this malady describe an intense,
uncomfortable sensation in the legs accompanied by an irresistible need to
move the legs, thus temporarily relieving their distress. The first
description of the disease dates back to the 1600’s, but it was Dr Ekbom
who first fully characterized the symptoms and brought the syndrome to the
attention of modern medicine. In 1995, an international group of researchers
further defined the syndrome by publishing guidelines for diagnosing RLS
using primary and associated features. Primary or obligate features must be
present to make a diagnosis of RLS while associated features are often
present, but are not necessary for the diagnosis.
Symptoms of RLS. The primary features of RLS include an urge to move the
legs driven by an unpleasant sensation, followed by a motor movement that
relieves, to some extent, the urge to move. Typically, the symptoms are
worse at rest, such as while sitting or lying down. Patients with RLS
frequently complain of difficulty sitting through a movie or riding for long
distances in a car or on a plane because of the intolerable sensations.
These feelings are described variably as crawling, prickling, burning,
aching, itching, or as something moving under the skin. There is also a
circadian rhythm to the disorder with the symptoms becoming most severe in
the evening and nighttime hours. Research has indicated that circadian
worsening is probably independent of the worsening associated with lying or
sitting at other times of the day.1
Associated features of RLS include periodic limb movements of sleep (PLMS).
These are repetitive limb movements that occur every 15 to 40 seconds during
non-REM sleep, often involving the legs, and at times causing sleep
disruption. Around 80% of patients with RLS will have concomitant PLMS.6 The
converse is not true so the presence of PLMS, especially in the elderly, is
not an indication of underlying restless legs syndrome. Aging is also
associated with worsening of RLS symptoms.11 More than one-third of patients
surveyed had their first symptoms occur before age 10, although most sought
medical attention decades later after their symptoms had progressed to
becoming bothersome.8 The most common sleep disturbance in RLS is sleep
onset insomnia with over 90% of patients reporting difficulty with sleep
initiation and/or maintenance.6
A positive family history is found in the majority of those with RLS, with
misdiagnosis common in the younger family members who are often felt to have
growing pains. Finally, the diagnosis of RLS should not be made in the
presence of other disorders that are known to cause secondary restlessness
of the legs.
Secondary RLS. The many causes of secondary RLS include lumbar stenosis13,
polyneuropathy,14, 15 pregnancy,16, 17 varicose veins,18 endstage renal
disease (ESRD), and uremia.19, 21. Laboratory abnormalities that have been
associated with RLS are anemia,22, iron deficiency and low serum ferritin
levels.23, 24 Thus, those with RLS symptoms require a thorough medical and
neurological examination and should have screening blood analysis to consist
of a complete blood count, serum chemistries, serum iron, ferritin, folate,
and vitamin B12 levels. Treatment of secondary RLS involves identifying the
underlying cause and treating the cause, if possible, including addressing
abnormal laboratory findings. For those with secondary RLS that do not
respond to treatment of the underlying condition, eg, RLS persisting in ESRD
after initiation of dialysis, then treatment of RLS should proceed as for
primary RLS.
Pathophysiology. The pathophysiologic basis of the sensory symptoms is
unknown, but recent studies have started to shed light on this very complex
problem. Magnetic resonance imaging (MRI) and electrophysiological studies
have not shown any structural abnormalities of the brainstem or cervical
spinal cord in those with RLS.4 Interestingly, functional MRI scanning in
patients with RLS demonstrates thalamic and cerebellar activation during the
abnormal sensations and additional activation in the brainstem and red
nuclei during movement.5 Voluntary movements did not duplicate these
findings. The involuntary nature of the movement disorder is further
confirmed by the lack of premovement cortical action potentials and a
subcortical or spinal origin is suggested.7 Trenkwalder, et al, conducted
electromyograms on patients with RLS observing that duration, periodicity,
and recruitment patterns of muscle jerks substantiate a spinal source.7
Treatment. Although no striatal dopamine deficiency has been found in a
recent PET study, 25 the most efficacious agents for this condition are
dopaminergic. Carbidopa-levodopa has proven to be very effective in
relieving manifestations of RLS even when evaluated in long-term use.26 It
works especially well in cases where RLS is accompanied by PLMS.27
Dyskinesias as a consequence of levodopa treatment do not develop in this
population; however, augmentation can limit levodopa therapy. Augmentation
refers to the occurrence of symptoms earlier and earlier during the day at
an intensity more severe than prior to levodopa use.28, 29 Increasing the
number of doses of levodopa will only worsen the problem; instead switching
to another dopaminergic medication is suggested. Dopamine agonists are
commonly used with good results in RLS. In a double-blind, crossover trial,
pergolide (Permax) was superior to levodopa for improving reported
restlessness and total sleep time.30 Pergolide has also shown good effects
over long treatment duration,31 and is less likely than levodopa to cause
augmentation.32 Preliminary trials using pramipexole (Mirapex) 33 and
ropinirole (Requip)34 are very encouraging. These agents have long
half-lives and have an advantage of maintaining better nighttime coverage
than levodopa.
Among first line agents for RLS are the opioids. This class of agents has
long been known to reduce symptoms of RLS, but there is reluctance from the
patient to take these drugs and also from the physician to prescribe them.
Usually, milder narcotics are given first. More potent opioids are reserved
for those whose fail initial treatment. There have been several double-blind
trials that have shown benefit, including a study using oxycodone that
showed improvement in sleep efficiency and PLMS with lessened arousals.35
Anticonvulsants, including gabapentin (Neurontin),36 carbamazepine (Tegretol),
and divalproex sodium (Depakote) have been used successfully in RLS and may
be tried as monotherapy or in adjunctive therapy for difficult cases.
Rounding out the list of first line agents in RLS are the benzodiazepines.
They may improve both symptoms of RLS and PLMS especially in mild cases.
Some patients can be managed for long periods of time on low dose
benzodiazepines without the occurrence of tolerance or the need for constant
medication adjustments. If patients do experience tolerance of unacceptable
dose escalation then try switching to a different class of agents.
Clonazepam (Klonopin) is probably the most widely used in doses between 0.5
mg to 3.0 mg per evening.
Medications are initiated prior to bedtime and an additional dose can be
given if the individual awakens with bothersome symptoms that interfere with
falling back to sleep. Inquire about late day restlessness, such as, while
watching the news or eating dinner, and dose accordingly. Dopaminergic
medications will have to be slowly titrated to benefit because of the
possible side effects of nausea, lowered blood pressure, dizziness, and
vivid dreams. Opioids and benzodiazepines in the elderly can cause imbalance
and dizziness.
Conclusion. The diagnosis of restless legs syndrome can be made with
accuracy by a physician familiar with the primary and associated features of
the condition. Secondary causes should be considered if there are unusual
features in the history, if there is no family history of RLS, or if the
neurological examination is abnormal. Generally, patients are willing to
undertake multiple trials to find a medication or combination of medications
that ameliorate symptoms and are very grateful when they are, at last,
relieved of
their torment.
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